Activation of cannabinoid type 2 (CB2) receptors promotes the maintenance of redox homeostasis and protects against oxidative distress in the Neotropical freshwater fish matrinxã Brycon amazonicus (Characiformes: Bryconidae)

Suzana Luisa Alves Fernandes¹, Yan Costa Gonçalves¹, Francisco Tadeu Rantin², Ana Lúcia Kalinin² and Diana Amaral Monteiro²

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Abstract​

Introduction​

Oxidative stress is broadly defined as an imbalance arising from the excessive formation of reactive oxygen species (ROS) compared to the capacity of cellular antioxidant defenses (Sies, Jones, 2007; Halliwell, Gutteridge, 2015). In cases of supraphysiological oxidative challenges, a disruption in the redox status occurs, leading to oxidative damage to biomolecules and resulting in a pathological state – a condition referred to as oxidative distress (Sies, 2019, 2020). On the other hand, the term oxidative eustress represents a controlled and beneficial form of oxidative challenge that occurs at a moderate and low-level physiological oxidative stress (Okegbe et al., 2012; Niki, 2016; Roach et al., 2018; Sies, 2020). It plays a pivotal role in life processes through redox signaling and regulation, whereby ROS acts as secondary messengers to trigger adaptive cellular responses (Sies, 2021; Sies et al., 2022). Maintaining a delicate balance between oxidative eustress and oxidative distress is crucial for cellular homeostasis and the overall health of the organism.

The endocannabinoid system includes two G-protein receptors identified as type 1 (CB1) and type 2 (CB2) (Castillo et al., 2012; Pisanti et al., 2013). The literature supports the positive effects associated with the activation of cannabinoid receptors, particularly CB2, in modulating ROS production under pathological conditions (Paloczi et al., 2018; Xin et al., 2020; Voicu et al., 2023). The imperative advancement of health applications in the field of applied redox biology necessitates the identification and exploration of mechanisms capable of adjusting the critical balance points between oxidative eustress and distress (Sies et al., 2022). In this context, investigating the mechanisms by which the activation of cannabinoid receptors modulates oxidative status holds scientific significance. This is particularly important because a comprehensive understanding of this phenomenon remains incomplete, especially under physiological conditions. Therefore, the regulation of the cannabinoid receptors through the administration of selective agonists emerges as a promising approach for both preventive and therapeutic strategies.

Oxidative distress is a critical factor affecting fish well-being and represents a significant challenge in aquaculture, especially in intensively managed culture systems that frequently elevate levels of stress (Hoseinifar et al., 2020; Song et al., 2023). Optimizing the efficiency and capacity of antioxidant defenses improves the modulation of immune responses and enhances disease resistance (Marmelo et al., 2024). Natural antioxidants (such as carotenoids, polyphenols, and vitamins) and synthetic antioxidants (including propyl gallate, tert-butylhydroquinone, butylated hydroxyanisole, and butylated hydroxytoluene) are commonly used to counteract the harmful effects of oxidative stress, with the goal of improving fish health (Hoseinifar et al., 2020; Pereira et al., 2022). While the use of synthetic antioxidants is increasingly restricted due to environmental and health safety concerns, the effectiveness of natural antioxidants relies on their structural properties, extraction methods, and stability under varying environmental conditions (e.g., light, temperature, and pH), necessitating rigorous risk-benefit analyses to ensure their safety and efficacy (Hoseinifar et al., 2020; Pereira et al., 2022; Petcu et al., 2023)

In our hypothesis, we propose that the activation of the CB2 receptor has the potential to positively modulate the oxidative status, thereby contributing to advantageous adaptations, that mitigate the potential harm caused by ROS in healthy animals. Therefore, this research aimed to explore the impact of activating CB1+CB2 receptors or exclusively CB2 receptors using suitable synthetic agonists on the antioxidant defense system and biomarkers of oxidative distress in key organs such as the liver and heart of Brycon amazonicus (Agassiz, 1829), a prominent freshwater fish species farmed in South America. In addition, fish represent a valuable alternative as an experimental model for evaluating innovative pre-clinical research, aligning with the 3Rs concept and offering advantages in terms of cost-effectiveness and ethical considerations.

Material and methods

Animals and treatment. Juvenile specimens (53.0 ± 3.4 g, mean ± SE) of Brycon amazonicus, known as matrinxã, were acquired from the Colpani fish farm (Mococa, SP, Brazil). The fish underwent a 30-day acclimatization period in 1000-liter holding tanks equipped with aerated and filtered water at a temperature of 25 ± 1 ºC and exposed to a natural photoperiod (12:12 light: dark cycle). Throughout the acclimatization phase, the fish were provided with ad libitum feeding of a commercial ration.

The fish were then allocated into three experimental groups: Control group (Ct; n = 15) – these specimens were administered an intraperitoneal (i.p.) injection of 0.5 ml of a vehicle solution (2.5% DMSO in sterile saline, Solbrig et al., 2013); 2) CB1+CB2-treated group (WIN; n= 15) – the fish received an i.p. injection of 1 mg.kg^-1 of the CB1+CB2 non-selective agonist WIN 55 212-2 (> 98% purity, Cayman Chemical), dissolved in vehicle solution; and 3) CB2-treated group (HU; n = 15) – the fish received an i.p. injection of 1 mg.kg^-1 of a CB2 receptor-selective agonist, HU 308 (> 98% purity, Cayman Chemical) dissolved in vehicle. Previous studies have demonstrated that the selected dosage exhibits anti-inflammatory effects (González et al., 2011; Wang et al., 2012). After 24 h, the fish were euthanized using an anesthetic overdose of benzocaine at a concentration of 0.3%. The hearts and livers were meticulously removed and rinsed with cold saline, then promptly frozen in liquid nitrogen and stored at -80°C until analyses were conducted.

Oxidative biomarkers. The liver and heart samples were homogenized (1:5 w/v) in a 0.1 M sodium-potassium phosphate buffer (pH 7.0) containing 1 mM phenylmethylsulfonyl fluoride (PMSF), then centrifuged at 10,000 g for 30 minutes at 4°C. The supernatants were utilized for the analyses described below. All readings were performed in duplicate at 25°C using either a UV-Vis spectrophotometer (BEL Engineering, Italy) or a microplate reader (Spectramax i3, Molecular Devices, USA).

Superoxide dismutase (SOD) activity was assessed following the method described by Flohé, Ötting (1984). The assay measures the rate of reduction of cytochrome c by superoxide anions at 550 nm. One unit of SOD corresponded to the enzyme amount that caused 50 % maximum inhibition of the cytochrome c reduction.

Catalase (CAT) activity was determinated by measuring the degradation of hydrogen peroxide (H₂O₂) at 240 nm according to the procedures described by Aebi (1974). One unit of CAT was defined as the quantity of enzyme required to release half of the peroxide oxygen within 100 seconds at 25°C (Bergmeyer unit – BU).

Glutathione peroxidase (GPx) activity was estimated in a reaction coupled with glutathione reductase (GR) and monitored by the decrease in absorbance of reduced NADPH at 340 nm (Nakamura et al., 1974). One unit of GPx was defined as the amount of enzyme needed to oxidize 1 μmol of NADPH per min.

Glutathione reductase (GR) activity was quantified in homogenates by monitoring the oxidation of NADPH at 340 nm in the presence of oxidized glutathione (GSSG) (Carlberg, Mannervik, 1985). One unit of GR corresponded to the enzyme amount that oxidized 1 μmol of NADPH per min.

Glutathione S-transferase (GST) activity was determined using 1-chloro-2,4- dinitrobenzene (CDNB) and reduced glutathione (GSH) (Habig et al., 1974). The rate of production of S-2, 4-dinitrophenyl glutathione was detected at 340 nm. One unit of GST corresponded to enzyme level responsible for the formation of 1 μmol of product per min.

The levels of reduced glutathione (GSH) and oxidized glutathione (GSSG) were determined using the 5,5’-dithiobis(2-nitrobenzoic acid) (DTNB)-GSSG reductase recycling assay as described by Anderson (1985). Homogenates were treated with 5% sulfosalicylic acid and centrifuged at 8,000 g for 5 minutes at 4°C. The production of thionitrobenzoic acid (TNB) was monitored at 412 nm to assess the levels of total glutathione (GSH plus GSSG). Specifically, GSSG levels were measured after treating homogenates with vinyl pyridine to sequester GSH (Cunha Bastos et al., 2007). Quantification of GSH and GSSG was performed in µmol per gram of tissue using standard curves. The GSH/GSSG ratio was defined by the formula: GSH/GSSG = [(GSH – 2*GSSG) / GSSG].

Lipoperoxidation (LPO) was assayed using the FOX-ferrous oxidation-xylenol orange method following the procedures reported by Jiang et al. (1992). This method involves the oxidation of Fe²⁺ by hydroperoxides in acidic samples, with the reaction catalyzed by orange xylenol, a Fe³⁺ complexing agent. The resulting complex was quantified at a wavelength of 560 nm. Lipid peroxidation (LPO) levels were then calculated using a standard curve of cumene hydroperoxide and expressed in nmol per mg of protein.

Protein carbonyl (PC) content was determined following the protocol outlined by Reznick, Packer (1994) using 2,4-dinitrophenylhydrazine (DNPH) and guanidine hydrochloride. The amount of carbonyl content was measured at 370 nm using the molar extinction coefficient of Ɛ₃₇₀ = 22 mM^-1 cm^-1 and expressed in nmol per mg of protein. Protein content in tissue homogenates was quantified at 595 nm using the Bradford method (Kruger, 1994), with bovine serum albumin as the standard.

Statistical analysis. Data are displayed as mean ± standard error (SE). Sample normality was verified employing the Kolmogorov-Smirnov method, and variance homogeneity was confirmed with Levene’s test. To identify significant differences between the experimental groups (Ct, WIN, and HU), a one-way analysis of variance (ANOVA) was conducted, followed by Tukey’s post hoc test for multiple comparisons (GraphPad Prism v. 8.0, GraphPad Software, USA). Differences between means were accepted as significant at p < 0.05.

Results​

The administration of the non-selective cannabinoid agonist (CB1+CB2), represented by the WIN group, caused a significant 29% decrease in hepatic SOD activity when compared to controls (Fig. 1A). Concurrently, the activities of CAT and GPx increased by 28% and 70%, respectively (Figs. 1B, C), while GST activity showed a significant decrease of 35%, coupled with a 30% reduction in GR activity (Figs. 1D, E, respectively). On the other hand, the HU group (CB2 activation) did not exhibit any significant changes in antioxidant enzyme activities compared to the Ct group.

FIGURE 1| Enzymatic activities of superoxide dismutase (SOD) (A), catalase (CAT) (B), glutathione peroxidase (GPx) (C), glutathione-S-transferase (GST) (D), and glutathione reductase (GR) (E) in the liver of Brycon amazonicus from control (Ct, n = 15), CB1+CB2-treated group (WIN, n = 15), and CB2-treated group (HU, n = 15). Mean values ± SE. Different letters indicate significant differences between groups (p < 0.05).

Regarding cardiac tissue, the WIN group demonstrated a significant enhancement in SOD (103%), CAT (73%), GPx (150%), and GST (54%) activities (Figs. 2A, B, C, D, respectively), along with a concomitant decrease in GR (44%) activity (Fig. 2E) compared to the Ct group. In contrast, the HU group showed no significant alterations in antioxidant enzymatic activities (Fig. 2) compared to the Ct group.

FIGURE 2| Enzymatic activities of superoxide dismutase (SOD) (A), catalase (CAT) (B), glutathione peroxidase (GPx) (C), glutathione-S-transferase (GST) (D), and glutathione reductase (GR) (E) in the heart of Brycon amazonicus from control (Ct, n = 15), CB1+CB2-treated group (WIN, n = 15), and CB2-treated group (HU, n = 15). Mean values ± SE. Different letters indicate significant differences between groups (p < 0.05).

In the context of the non-enzymatic GSH system, the WIN group demonstrated a significant decline in hepatic GSH levels (37%) while showing no alterations in ventricular GSH content compared to the Ct group (Figs. 3A and D, respectively). Meanwhile, the HU group exhibited no alterations in hepatic GSH content but showed a significant increase in ventricular GSH levels (115%) compared to the Ct group (Figs. 3A and D, respectively). Regarding GSSG contents, the CB1+CB2 agonist induced a significant 37% increase in ventricular GSSG levels, with no substantial change in hepatic tissue (Figs. 3B and E, respectively). In contrast, the HU group displayed a reduction in both hepatic (33%) and cardiac (53%) GSSG contents compared to the Ct group (Figs. 3B and E, respectively). The GSH:GSSG ratio remained unchanged in the hepatic and cardiac tissues of the WIN group. Nevertheless, this ratio showed a substantial increase in the liver (112%) and heart (606%) of the HU group compared to controls (see Figs. 3 C and F, respectively).

FIGURE 3| Hepatic and cardiac levels of reduced (GSH) (A and D, respectively) and oxidized (GSSG) (B and E, respectively) glutathione, and GSH/GSSG ratio (C and F, respectively) of Brycon amazonicus from control (Ct, n = 15), CB1+CB2-treated group (WIN, n = 15), and CB2-treated group (HU, n = 15). Mean values ± SE. Different letters indicate significant differences between groups (p < 0.05).

Oxidative stress analysis revealed that the WIN group did not exhibit changes in hepatic LPO levels compared to controls (Fig. 4A). However, the PC content showed a significant increase (51%) (Fig. 4B). In the cardiac tissue, both LPO and PC levels increased by 70% and 99%, respectively (Figs. 4C, D, respectively). Conversely, in comparison to the Ct group, HU treatment resulted in a significant decrease in hepatic LPO levels (33%) (Fig. 4C), with no significant alterations in hepatic PC content (Fig. 4A) or in cardiac LPO and PC levels (Figs. 4C, D, respectively).

FIGURE 4| Lipid peroxidation (LPO) and protein carbonyl (PC) levels in the liver (A and B, respectively) and the heart (C and D, respectively) of Brycon amazonicus from control (Ct, n = 15), CB1+CB2-treated group (WIN, n = 15), and CB2-treated group (HU, n = 15). Mean values ± SE. Different letters indicate significant differences between groups (p < 0.05).

Discussion​

This is one of the first studies to demonstrate the effects of both cannabinoid receptor activation, CB1 and CB2, as well as selective activation of CB2, on the redox balance of two crucial organs: the liver and the heart, under physiological conditions. The comprehension of the antioxidative properties resulting from the activation of CB1 and CB2 receptors is crucial for employing agonists as a therapeutic approach in the prevention and treatment of disorders related to oxidative distress. This study demonstrated that acute treatment with the CB1/CB2 agonist WIN 55,212-2, resulted in a shift of the redox balance from eustress to distress, both in the liver and in the heart. On the other hand, the acute administration of the selective CB2 receptor agonist HU-308 exhibited antioxidant properties in both vital organs, contributing to the maintenance of oxidative eustress.

Cannabinoid receptors activate various intracellular signaling pathways, adding complexity and bias to our understanding of their role in regulating oxidative signaling and metabolic abnormalities (Ibsen et al., 2017; Soethoudt et al., 2017; Saroz et al., 2019). Although it is still unclear which specific CB1 and CB2 signaling pathways are activated, there is a growing acknowledgment that, under various pathological processes, the activation of CB1 receptors might trigger c-jun n-terminal kinase (JNK) and p38 mitogen activated protein kinase (p38 MAPK) signaling cascades, which are known to be related in cell death, ROS generation, and inflammatory response, contributing to the development of cardiac and hepatic dysfunctions (Mukhopadhyay et al., 2010; Rajesh et al., 2012; Tian et al., 2017; Kim et al., 2020; Jorgačević et al., 2021). Conversely, CB2 signaling demonstrates the ability to selectively activate the protein kinase 1 and 2 (ERK1/2) nuclear factor erythroid 2-related factor 2 (Nrf2) pathway. These pathways are intricately associated with antifibrogenic and anti-inflammatory functions, ultimately resulting in cardio- and hepatoprotective effects (Lépicier et al., 2003; Montecucco et al., 2009; Teixeira-Clerc et al., 2010; Montecucco, Di Marzo, 2012; Steffens, Pacher, 2012; Wang et al., 2014; Hashiesh et al., 2021). Therefore, CB2 stimulation appears to dynamically modulate numerous pathophysiological processes and is implicated in the regulation of various pathological conditions (Tabrizi et al., 2016; Shang, Tang, 2017; Hashiesh et al., 2021).

Our results demonstrated that CB2 activation modulates the balance between oxidative eustress and distress even under physiological conditions, which would be highly relevant for hepatic and cardiac survival when homeostasis is lost. Considering that ROS plays a pivotal role in cell function (Sinenko et al., 2021; Sharma et al., 2023), the positive modulation of CB2-induced oxidative eustress contributes to tissue integrity and the normal functioning of physiological processes. Redox signaling refers to oxidation/reduction modifications of cellular signaling components, capable of regulate gene expression, excitation-contraction coupling, regeneration, cell growth, migration, differentiation, and apoptosis (Sack et al., 2017; Dubois-Deruy et al., 2020). Consequently, the production and maintenance of controlled levels of intracellular ROS mediated by CB2 receptor activation, preserving redox homeostasis, holds the potential to ameliorate or prevent disease progression.

The treatment of HU-308 reduced ROS production in the liver, thereby mitigating LPO injuries and preserving PC levels in both cardiac and hepatic tissues. In zebrafish Danio rerio (Hamilton, 1822), inhibition of CB2 receptor activity using the antagonist AM630 disrupts liver function, suggesting that the endocannabinoid system is involved in the regulation of lipid homeostasis (Liu et al., 2016). The antioxidant effect observed upon CB2 activation in matrinxã was associated with an increase in the GSH/GSSG ratio, achieved by elevating GSH levels and/or inhibiting GSSG production, all while preserving the activities of antioxidant enzymes. Previous studies have reported that stimulation of CB2 receptors by synthetic agonists promotes cardioprotection and hepatoprotection through downstream activation via Nrf2 pathways (Li et al., 2016; Hashiesh et al., 2021; More et al., 2024). This activation leads to the inhibition of oxidative stress, prevention of apoptotic cell death and fibrosis, reduced lesion area, and attenuation of the release of inflammatory cytokines in ischemia/reperfusion or toxicant-induced liver injury (Rajesh et al., 2007; Montecucco et al., 2009; Louvet et al., 2011; Li et al., 2014; Wu et al., 2019; Yu et al., 2019; González-Candia et al., 2022). Nrf2 is a redox-sensitive transcription factor responsible for maintaining redox homeostasis by modulating antioxidant-response element (ARE)-dependent transcription and subsequently expressing enzymes involved in antioxidant defense (Kang et al., 2020). This process enhances the antioxidant capacity, both enzymatic and non-enzymatic, in a compensatory manner in response to an increase in ROS (González-Candia et al., 2022).

By reducing ROS levels, HU-308 also safeguards GSH levels, preventing their oxidation, as evidenced by the increased GSH/GSSG ratio in cardiac and hepatic tissues. This is of great practical importance because GSH plays vital roles in shielding cells from oxidative harm, neutralizing the toxicity of foreign chemical electrophiles, and preserving redox balance (Forman et al., 2009; Atalay et al., 2020). Fouad et al. (2013) observed a significant reduction in lipid peroxidation (LPO), maintenance of GSH levels, and decreased production of tumor necrosis factor-alpha (TNF-α) and nitric oxide (NO) in the cardiac tissue of rats exposed to doxorubicin cardiotoxicity following treatment with cannabidiol, which has been associated with CB2 activation (Martínez-Pinilla et al., 2017). Cannabidiol supplementation at 100 and 250 mg kg^-1 in high soybean oil diets significantly increased liver antioxidant defenses, including peroxidase and superoxide dismutase activities and total antioxidant capacity, while concurrently reducing lipid peroxidation and inhibiting inflammatory gene expression in large yellow croaker Larimichthys crocea (Richardson, 1846) (Wang et al., 2023). Cannabidiol treatment (5 mg/kg, i.p.) also provided protection against oxidative stress induced by the organophosphate insecticide chlorpyrifos in the brain of goldfish Carassius auratus (Linnaeus, 1758) (Gómez-Vega, González-Mantilla, 2023).

In our previous investigation, utilizing the fish species B. amazonicus as an experimental model, HU-308 treatment significantly enhanced ventricular contractility, inducing positive inotropic and lusitropic responses attributed to increased cAMP levels and Ca²⁺-handling protein expression (Gonçalves et al., 2024). The preservation of redox homeostasis and prevention of oxidative distress in cardiomyocytes following HU-308 treatment could also contribute to an enhancement in cardiac performance. Given the pivotal role of oxidative distress in driving contractile dysfunction, the activation of antioxidant systems, especially the GSH system, is crucial for protecting cardiomyocytes from oxidative damage (Tan et al., 2023). Excessive ROS can damage all major cellular components (DNA, proteins, and lipids), resulting in altered Ca²⁺ regulation and activation of pathways associated with apoptosis, promotion of fibrosis, and inflammatory responses (Aimo et al., 2020). For instance, ryanodine receptors, which release Ca²⁺ from the sarcoplasmic reticulum, demonstrate sensitivity to changes in cellular redox status, showing inhibition under conditions characterized by a high GSH/GSSG ratio and activation in the presence of a low GSH/GSSG ratio (Poluektov et al., 2019).

Conversely, the non-selective agonist WIN 55,212-2 induced oxidative distress, as represented by elevated levels of LPO and/or PC in the liver and heart. Previous research has also shown that specific CB1 stimulation directly induces intracellular ROS generation and initiates inflammatory responses through the p38-MAPK pathway in various tissues (Han et al., 2009; Mukhopadhyay et al., 2010; Rajesh et al., 2010; Tiyerili et al., 2010; Zoppi et al., 2011; Guillamat-Prats et al., 2019), resulting in an exacerbation of redox imbalance. Additionally, the CB1+CB2 treatment increased the activity of antioxidant enzymes CAT and GPx while inhibiting GR activity in both tissues. In the heart, it also triggered increased activities of SOD and GST, while causing a decrease in their activities in the liver. The increased activity of enzymes such as CAT, GPx, and SOD indicates the generation of ROS, primarily the superoxide anion and hydrogen peroxide. Given their inhibitory effect on oxyradical formation, the SOD-CAT and GPx systems constitute the primary defenses against oxygen toxicity (Ighodaro, Akinloye, 2018). The reduced activity of hepatic SOD could be related to the excessive production of hydrogen peroxide (Perry et al., 2010; Gottfredsen et al., 2013). The inhibition of hepatic and cardiac GR activity following CB1+CB2 agonist treatment is intricately linked to the increased cardiac GSSG levels or the reduction of hepatic GSH content and GST activity. GST catalyzes the conjugation of GSH with electrophiles, thereby protecting organisms against genotoxic and carcinogenic compounds (Lushchak, 2012). Under these conditions, GSH depletion and GST inhibition made the hepatocyte more vulnerable to oxidative damage, consequently leading to higher levels of PC.

Corroborating our findings, CB1 blockade attenuated hepatic oxidative/nitrosative stress parameters and improved liver histology in mice with nonalcoholic fatty liver disease (Jorgačević et al., 2015). On the other hand, CB1 overexpression induces hepatic lipid accumulation in larval and adult zebrafish and promotes lipotoxicity (Pai et al., 2013). Several studies also provide evidence indicating that the stimulation of CB1 receptors can either promote or facilitate oxidative distress, inflammation, and cell death in models of cardiomyopathies (Mukhopadhyay et al., 2007, 2010; Rajesh et al., 2012), as well as in human coronary artery endothelial cells (Rajesh et al., 2010).

Because WIN 55,212-2 functions as a non-selective agonist for CB1 and CB2 receptors, it appears that CB1 receptor activation may have triggered a compensatory mechanism to counterbalance the positive effects of CB2 receptor activation. This phenomenon has been documented in cases of both acute and chronic kidney diseases, where the activation of CB2 induces anti-inflammatory responses and reduces fibrosis, whereas signaling through the CB1 receptor induces oxidative distress, inflammation, and cell apoptosis (Barutta et al., 2018; Hokmabadi et al., 2023).

This study is the first to investigate how cannabinoid receptor activation affects the balance between oxidative distress and eustress in healthy animals, revealing an interaction between the endocannabinoid system and the antioxidant defense system under physiological conditions (Fig. 5). The modulation through CB2 can effectively counteract disruptions in redox homeostasis, mitigating ROS formation and preventing oxidative damage. On the other hand, CB1 activation led to an imbalance resulting in adverse outcomes and oxidative distress, which can potentially contribute to the progress and/or aggravation of various diseases. Therefore, CB2 receptor emerges as a promising therapeutic target for developing strategies focused on enhancing antioxidant defense, redirecting inflammatory signaling, facilitating hypoxia adaptation, and enhancing the overall health status of fish.

FIGURE 5| The diagram illustrates the impact of both CB1+CB2 and CB2 activation on oxidative stress in liver (right side) and heart (left side) cells of Brycon amazonicus. Arrows indicate increases or decreases in non-enzymatic antioxidant levels, antioxidant enzymatic activities, and oxidative stress biomarkers. Equal symbols (=) denote the constancy of these parameters. Blue symbols represent the CB2-treated group (HU) exhibiting oxidative eustress effects, whereas red symbols denote the CB1+ CB2-treated group (WIN) demonstrating oxidative distress effects. Red and blue dotted arrows indicate the potential signaling pathways of CB1 and CB2 receptors, respectively. CB1: cannabinoid receptor type 1; CB2: cannabinoid receptor type 2; GSH: reduced glutathione; GSSG: oxidized glutathione; SOD: superoxide dismutase; CAT: catalase; GPx: glutathione peroxidase; GR: glutathione reductase; GST: glutathione-S-transferase; LPO: lipoperoxidation level; PC: Protein carbonyl content.

Acknowledgments​

This research was supported by the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq 404688/2018–7, CNPq/PQ 301809/2022–4, INCT-Peixes 405706/2022–7, SFAL fellowship 130995/2022–3) and the Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2020/13382–2). The authors gratefully acknowledge Colpani fish farm for supplying the fish utilized in this study.

References​

Aebi H. Catalase. In: Bergmeyer HU, editor. Methods of enzymatic analysis. NewYork: Academic Press Inc.; 1974. p.673–80. https://doi.org/10.1016/b978-0-12-091302-2.50032-3

Aimo A, Castiglione V, Borrelli C, Saccaro LF, Franzini M, Masi S et al.Oxidative stress and inflammation in the evolution of heart failure: from pathophysiology to therapeutic strategies. Eur J Prev Cardiol. 2020; 27(5):494–510. https://doi.org/10.1177/2047487319870344

Anderson ME. Determination of glutathione and glutathione disulfide in biological samples. Methods Enzymol. 1985; 113:548–55. https://doi.org/10.1016/S0076-6879(85)13073-9

Atalay S, Jarocka-Karpowicz I, Skrzydlewska E. Antioxidative and anti-inflammatory properties of cannabidiol. Antioxidants. 2020; 9(1):21. https://doi.org/10.3390/antiox9010021

Barutta F, Bruno G, Mastrocola R, Bellini S, Gruden G. The role of cannabinoid signaling in acute and chronic kidney diseases. Kidney Int. 2018; 94(2):252–58. https://doi.org/10.1016/j.kint.2018.01.024

Carlberg I, Mannervik B. Glutathione reductase. Methods Enzymol. 1985; 113:484–90. https://doi.org/10.1016/S0076-6879(85)13062-4

Castillo PE, Younts TJ, Chávez AE, Hashimotodani Y. Endocannabinoid signaling and synaptic function. Neuron. 2012; 76(1):70–81. https://doi.org/10.1016/j.neuron.2012.09.020

Cunha Bastos VLF, Salles JB, Valente RH, León IR, Perales J, Dantas RF et al. Cytosolic glutathione peroxidase from liver of pacu (Piaractus mesopotamicus), a hypoxia-tolerant fish of the Pantanal. Biochimie. 2007; 89(11):1332–42. https://doi.org/10.1016/j.biochi.2007.04.003

Dubois-Deruy E, Peugnet V, Turkieh A, Pinet F. Oxidative stress in cardiovascular diseases. Antioxidants. 2020; 9(9):864. https://doi.org/10.3390/antiox9090864

Flohé L, Ötting F. Superoxide dismutase assays. Methods Enzymol. 1984; 105:93–104. https://doi.org/10.1016/S0076-6879(84)05013-8

Forman HJ, Zhang H, Rinna A. Glutathione: overview of its protective roles, measurement, and biosynthesis. Mol Aspects Med. 2009; 30(1–2):1–12. https://doi.org/10.1016/j.mam.2008.08.006

Fouad AA, Albuali WH, Al-Mulhim AS, Jresat I. Cardioprotective effect of cannabidiol in rats exposed to doxorubicin toxicity. Environ Toxicol Pharmacol. 2013; 36(2):347–57. https://doi.org/10.1016/j.etap.2013.04.018

Gómez-Vega AP, González-Mantilla JF. Antioxidant effects of the phytocannabinoid cannabidiol (CBD) in the brain of chlorpyrifos-exposed goldfish (Carassius auratus). OARJLS. 2023; 6:8–16. https://doi.org/10.53022/oarjls.2023.6.1.0044

Gonçalves YC, Campos KCF, Vasconcelos ES, D’Almeida Eça BM, Rantin FT, Kalinin AL et al. Activation of the cannabinoid type 2 (CB2) receptor improves cardiac contractile performance in fish, Brycon amazonicus. Comp Biochem Physiol C Toxicol Pharmacol. 2024; 277:109822. https://doi.org/10.1016/j.cbpc.2023.109822

González C, Herradón E, Abalo R, Vera G, Pérez-Nievas BG, Leza JC et al. Cannabinoid/agonist WIN 55,212-2 reduces cardiac ischaemia–reperfusion injury in Zucker diabetic fatty rats: role of CB2 receptors and iNOS/eNOS. Diabetes Metab Res Rev. 2011; 27(4):331–40. https://doi.org/10.1002/dmrr.1176

González-Candia A, Candia AA, Paz A, Mobarec F, Urbina-Varela R, del Campo A et al. Cardioprotective antioxidant and anti-inflammatory mechanisms induced by intermittent hypobaric hypoxia. Antioxidants. 2022; 11(6):1043. https://doi.org/10.3390/antiox11061043

Gottfredsen RH, Larsen UG, Enghild JJ, Petersen SV. Hydrogen peroxide induces modifications of human extracellular superoxide dismutase that results in enzyme inhibition. Redox Biol. 2013; 1(1):24–31. https://doi.org/10.1016/j.redox.2012.12.004

Guillamat-Prats R, Rami M, Herzig S, Steffens S. Endocannabinoid signalling in atherosclerosis and related metabolic complications. J Thromb Haemost. 2019; 119(4):567–75. https://doi.org/10.1055/s-0039-1678738

Habig WH, Pabst MJ, Jakoby WB. Glutathione S-transferases. The first enzymatic step in mercapturic acid formation. J Biol Chem. 1974; 249(22):7130–39. https://doi.org/10.1016/S0021-9258(19)42083-8

Halliwell B, Gutteridge JM. Free radicals in biology and medicine, fifth ed. New York: Oxford University Press; 2015.

Han KH, Lim S, Ryu J, Lee C-W, Kim Y, Kang J-H et al. CB1 and CB2 cannabinoid receptors differentially regulate the production of reactive oxygen species by macrophages. Cardiovasc Res. 2009; 84(3):378–86. https://doi.org/10.1093/cvr/cvp240

Hashiesh HM, Sharma C, Goyal SN, Jha NK, Ojha S. Pharmacological properties, therapeutic potential and molecular mechanisms of JWH133, a CB2 receptor-selective agonist. Front Pharmacol. 2021; 12:702675. https://doi.org/10.3389/fphar.2021.702675

Hokmabadi V, Khalili A, Hashemi SA, Hedayatyanfard K, Parvari S, Changizi-Ashtiyani S et al. Cannabidiol interacts with the FXR/Nrf2 pathway and changes the CB1/CB2 receptors ratio in gentamicin-induced kidney injury in rats. Iran J Basic Med Sci. 2023; 26(3):343–50. https://doi.org/10.22038/IJBMS.2023.67998.14867

Hoseinifar SH, Yousefi S, Van Doan H, Ashouri G, Gioacchini G, Maradonna F et al. Oxidative stress and antioxidant defense in fish: the implications of probiotic, prebiotic, and synbiotics. Rev Fish Sci Aquac. 2020; 29(2):198–217. https://doi.org/10.1080/23308249.2020.1795616

Ibsen MS, Connor M, Glass M. Cannabinoid CB1 and CB2 receptor signaling and bias. Cannabis Cannabinoid Res. 2017; 2(1):48–60. https://doi.org/10.1089/can.2016.0037

Ighodaro OM, Akinloye OA. First line defence antioxidants-superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX): their fundamental role in the entire antioxidant defence grid. Alex J Med. 2018; 54(4):287–93. https://doi.org/10.1016/j.ajme.2017.09.001

Jiang Z-Y, Hunt JV, Wolff SP. Ferrous ion oxidation in the presence of xylenol orange for detection of lipid hydroperoxide in low density lipoprotein. Anal Biochem. 1992; 202(1):384–89. https://doi.org/10.1016/0003-2697(92)90122-N

Jorgačević B, Mladenović D, Ninković M, Vesković M, Dragutinović V, Vatazević A et al. Rimonabant improves oxidative/nitrosative stress in mice with nonalcoholic fatty liver disease. Oxid Med Cell Longev. 2015; 842108. https://doi.org/10.1155/2015/842108

Jorgačević B, Vučević D, Samardžić J, Mladenović D, Vesković M, Vukićević D et al. The effect of CB1 antagonism on hepatic oxidative/nitrosative stress and inflammation in nonalcoholic fatty liver disease. Curr Med Chem. 2021; 28(1):169–80. https://doi.org/10.2174/0929867327666200303122734

Kang T-C. Nuclear factor-erythroid 2-related factor 2 (Nrf2) and mitochondrial dynamics/mitophagy in neurological diseases. Antioxidants. 2020; 9(7):617. https://doi.org/10.3390/antiox9070617

Kim Y, Gautam S, Aseer KR, Kim J, Chandrasekaran P, Mazucanti CH et al. Hepatocyte cannabinoid 1 receptor nullification alleviates toxin-induced liver damage via NF-κB signaling. Cell Death Dis. 2020; 11:1044. https://doi.org/10.1038/s41419-020-03261-8

Kruger NJ. The Bradford method for protein quantitation. Methods Mol Biol. 1994; 32:9–15. https://doi.org/10.1385/0-89603-268-X:9

Lépicier P, Bouchard J-F, Lagneux C, Lamontagne D. Endocannabinoids protect the rat isolated heart against ischaemia. Br J Pharmacol. 2003; 139(4):805–15. https://doi.org/10.1038/sj.bjp.0705313

Li Q, Guo H-C, Maslov LN, Qiao X-W, Zhou J-J, Zhang Y. Mitochondrial permeability transition pore plays a role in the cardioprotection of cb2 receptor against ischemia-reperfusion injury. Can J Physiol Pharmacol. 2014; 92(3):205–14. https://doi.org/10.1139/cjpp-2013-0293

Li X, Han D, Tian Z, Gao B, Fan M, Li C et al. Activation of cannabinoid receptor type II by AM1241 ameliorates myocardial fibrosis via Nrf2-mediated inhibition of TGF-β1/smad3 pathway in myocardial infarction mice. Cell Physiol Biochem. 2016; 39(4):1521–36. https://doi.org/10.1159/000447855

Liu LY, Alexa K, Cortes M, Schatzman-Bone S, Kim AJ, Mukhopadhyay B et al. Cannabinoid receptor signaling regulates liver development and metabolism. Development. 2016; 143:609–22. https://doi.org/10.1242/dev.121731

Louvet A, Teixeira-Clerc F, Chobert M-N, Deveaux V, Pavoine C, Zimmer A et al. Cannabinoid CB2 receptors protect against alcoholic liver disease by regulating Kupffer cell polarization in mice. Hepatology. 2011; 54(4):1217–26. https://doi.org/10.1002/hep.24524

Lushchak VI. Glutathione homeostasis and functions: potential targets for medical interventions. J Amino Acids. 2012; 736837. https://doi.org/10.1155/2012/736837

Marmelo I, Dias M, Grade A, Pousão-Ferreira P, Diniz MS, Marques A et al. Immunomodulatory and antioxidant effects of functional aquafeeds biofortified with whole Laminaria digitata in juvenile gilthead seabream (Sparus aurata). Front Mar Sci. 2024; 11:1325244. https://doi.org/10.3389/fmars.2024.1325244

Martínez-Pinilla E, Varani K, Reyes-Resina I, Angelats E, Vincenzi F, Ferreiro-Vera C, et al. Binding and signaling studies disclose a potential allosteric site for cannabidiol in cannabinoid CB₂ receptors. Front Pharmacol. 2017; 8:744. https://doi.org/10.3389/fphar.2017.00744

Montecucco F, Di Marzo V. At the heart of the matter: the endocannabinoid system in cardiovascular function and dysfunction. Trends Pharmacol Sci. 2012; 33(6):331–40. https://doi.org/10.1016/j.tips.2012.03.002

Montecucco F, Lenglet S, Braunersreuther V, Burger F, Pelli G, Bertolotto M et al. CB2 Cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion. J Mol Cell Cardiol. 2009; 46(5):612–20. https://doi.org/10.1016/j.yjmcc.2008.12.014

More SA, Deore RS, Pawar HD, Sharma C, Nakhate KT, Rathod SS et al. CB2 cannabinoid receptor as a potential target in myocardial infarction: exploration of molecular pathogenesis and therapeutic strategies. Int J Mol Sci. 2024; 25(3):1683. https://doi.org/10.3390/ijms25031683

Mukhopadhyay P, Bátkai S, Rajesh M, Czifra N, Harvey-White J, Haskó G et al. Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. J Am Coll Cardiol. 2007; 50(6):528–36. https://doi.org/10.1016/j.jacc.2007.03.057

Mukhopadhyay P, Rajesh M, Bátkai S, Patel V, Kashiwaya Y, Liaudet L et al. CB1 cannabinoid receptors promote oxidative stress and cell death in murine models of doxorubicin-induced cardiomyopathy and in human cardiomyocytes. Cardiovasc Res. 2010; 85:773–84. https://doi.org/10.1093/cvr/cvp369

Nakamura W, Hosoda S, Hayashi K. Purification and properties of rat liver glutathione peroxidase. Biochim Biophys Acta. 1974; 358(2):251–61. https://doi.org/10.1016/0005-2744(74)90455-0

Niki E. Oxidative stress and antioxidants: distress or eustress? Arch Biochem Biophys. 2016; 595:19–24. https://doi.org/10.1016/j.abb.2015.11.017

Okegbe C, Sakhtah H, Sekedat MD, Price-Whelan A, Dietrich LEP. Redox eustress: roles for redox-active metabolites in bacterial signaling and behavior. Antioxid Redox Signal. 2012; 16(7):658–67. https://doi.org/10.1089/ars.2011.4249

Pai W-Y, Hsu C-C, Lai C-Y, Chang T-Z, Tsai Y-L, Her GM. Cannabinoid receptor 1 promotes hepatic lipid accumulation and lipotoxicity through the induction of SREBP-1c expression in zebrafish. Transgenic Res. 2013; 22:823–38. https://doi.org/10.1007/s11248-012-9685-0

Paloczi J, Varga ZV, Hasko G, Pacher P. Neuroprotection in oxidative stress-related neurodegenerative diseases: role of endocannabinoid system modulation. Antioxid Redox Signal. 2018; 29(1):75–108. https://doi.org/10.1089/ars.2017.7144

Pereira R, Costa M, Velasco C, Cunha LM, Lima RC, Baião LF et al. Comparative analysis between synthetic vitamin E and natural antioxidant sources from tomato, carrot and coriander in diets for market-sized Dicentrarchus labrax. Antioxidants. 2022; 11(4):636. https://doi.org/10.3390/antiox11040636

Perry JJP, Shin DS, Getzoff ED, Tainer JA. The structural biochemistry of the superoxide dismutases. Biochim Biophys Acta. 2010; 1804(2):245–62. https://doi.org/10.1016/j.bbapap.2009.11.004

Petcu CD, Mihai OD, Tăpăloagă D, Gheorghe-Irimia R-A, Pogurschi EN et al. Effects of plant-based antioxidants in animal diets and meat products: a review. Foods. 2023; 12(6):1334. https://doi.org/10.3390/foods12061334

Pisanti S, Picardi P, D’Alessandro A, Laezza C, Bifulco M. The endocannabinoid signaling system in cancer. Trends Pharmacol Sci. 2013; 34(5):273–82. https://doi.org/10.1016/j.tips.2013.03.003

Poluektov YM, Petrushanko IY, Undrovinas NA, Lakunina VA, Khapchaev AY, Kapelko VI et al. Glutathione-related substances maintain cardiomyocyte contractile function in hypoxic conditions. Sci Rep. 2019; 9:4872. https://doi.org/10.1038/s41598-019-41266-2

Rajesh M, Bátkai S, Kechrid M, Mukhopadhyay P, Lee W-S, Horváth B et al. Cannabinoid 1 receptor promotes cardiac dysfunction, oxidative stress, inflammation, and fibrosis in diabetic cardiomyopathy. Diabetes. 2012; 61(3):716–27. https://doi.org/10.2337/db11-0477

Rajesh M, Mukhopadhyay P, Bátkai S, Haskó G, Liaudet L, Huffman JW et al. CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion. Am J Physiol Heart Circ Physiol. 2007; 293(4):2210–18. https://doi.org/10.1152/ajpheart.00688.2007

Rajesh M, Mukhopadhyay P, Haskó G, Liaudet L, Mackie K, Pacher P. Cannabinoid-1 receptor activation induces reactive oxygen species-dependent and -independent mitogen-activated protein kinase activation and cell death in human coronary artery endothelial cells. Br J Pharmacol. 2010; 160(3):688–700. https://doi.org/10.1111/j.1476-5381.2010.00712.x

Reznick AZ, Packer L. Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Methods Enzymol. 1994; 233:357–63. https://doi.org/10.1016/S0076-6879(94)33041-7

Roach T, Stoggl W, Baur T, Kranner I. Distress and eustress of reactive electrophiles and relevance to light stress acclimation via stimulation of thiol/disulphide-based redox defences. Free Radic Biol Med. 2018; 122:65–73. https://doi.org/10.1016/j.freeradbiomed.2018.03.030

Sack MN, Fyhrquist FY, Saijonmaa OJ, Fuster V, Kovacic JC. Basic biology of oxidative stress and the cardiovascular system: Part 1 of a 3-part series. J Am Coll Cardiol. 2017; 70(2):196–211. https://doi.org/10.1016/j.jacc.2017.05.034

Saroz Y, Kho DT, Glass M, Graham ES, Grimsey NL. Cannabinoid receptor 2 (CB₂) signals via G-alpha-s and induces IL-6 and IL-10 cytokine secretion in human primary leukocytes. ACS Pharmacol Transl Sci. 2019; 2(6):414–28. https://doi.org/10.1021/acsptsci.9b00049

Shang Y, Tang Y. The central cannabinoid receptor type-2 (CB2) and chronic pain. Int J Neurosci. 2017; 127(9):812–23. https://doi.org/10.1080/00207454.2016.1257992

Sharma P, Nandave M, Nandave D, Yadav S, Vargas-De-La-Cruz C, Singh S et al. Reactive oxygen species (ROS)-mediated oxidative stress in chronic liver diseases and its mitigation by medicinal plants. Am J Transl Res. 2023; 15(11):6321–41.

Sies H. Oxidative stress: eustress and distress in redox homeostasis. In: Fink G, editor. Stress: physiology, biochemistry, and pathology. London: Academic Press; 2019. p.153–63. https://doi.org/10.1016/B978-0-12-813146-6.00013-8

Sies H. Oxidative eustress and oxidative distress: introductory remarks. In: Sies H, editor. Oxidative stress. London: Academic Press; 2020. p.3–12. https://doi.org/10.1016/B978-0-12-818606-0.00001-8

Sies H. Oxidative eustress: on constant alert for redox homeostasis. Redox Biol. 2021; 41:101867. https://doi.org/10.1016/j.redox.2021.101867

Sies H, Belousov VV, Chandel NS, Davies MJ, Jones DP, Mann GE et al.Defining roles of specific reactive oxygen species (ROS) in cell biology and physiology. Nat Rev Mol Cell Biol. 2022; 23:499–515. https://doi.org/10.1038/s41580-022-00456-z

Sies H, Jones DP. Oxidative stress. In: Fink G, editor. Encyclopedia of stress, 2nd edn. Amsterdam: Elsevier; 2007. p.45–48.

Sinenko SA, Starkova TY, Kuzmin AA, Tomilin AN. Physiological signaling functions of reactive oxygen species in stem cells: from flies to man. Front Cell Dev Biol. 2021; 9:714370. https://doi.org/10.3389/fcell.2021.714370

Soethoudt M, Grether U, Fingerle J, Grim TW, Fezza F, Petrocellis L et al.Cannabinoid CB2 receptor ligand profiling reveals biased signaling and off target activity. Nat Commun. 2017; 8:13958. https://doi.org/10.1038/ncomms13958

Solbrig MV, Fan Y, Hazelton P. Prospects for cannabinoid therapies in viral encephalitis. Brain Res. 2013; 1537:273–82. https://doi.org/10.1016/j.brainres.2013.08.032

Song C, Sun C, Liu B, Xu P. Oxidative stress in aquatic organisms. Antioxidants. 2023; 12(6):1223. https://doi.org/10.3390/antiox12061223

Steffens S, Pacher P. Targeting cannabinoid receptor CB(2) in cardiovascular disorders: promises and controversies. Br J Pharmacol. 2012; 167(2):313–23. https://doi.org/10.1111/j.1476-5381.2012.02042.x

Tabrizi AM, Baraldi PG, Borea PA, Varani K. Medicinal chemistry, pharmacology, and potential therapeutic benefits of cannabinoid CB2 receptor agonists. Chem Rev. 2016; 116(2):519–60. https://doi.org/10.1021/acs.chemrev.5b00411

Tan M, Yin Y, Ma X, Zhang J, Pan W, Tan M et al.Glutathione system enhancement for cardiac protection: pharmacological options against oxidative stress and ferroptosis. Cell Death Dis. 2023; 14:131. https://doi.org/10.1038/s41419-023-05645-y

Teixeira-Clerc F, Belot M-P, Manin S, Deveaux V, Cadoudal T, Chobert M-N et al.Beneficial paracrine effects of cannabinoid receptor 2 on liver injury and regeneration. Hepatology. 2010; 52(3):1046–59. https://doi.org/10.1002/hep.23779

Tian L, Li W, Yang L, Chang N, Fan X, Ji X et al.Cannabinoid receptor 1 participates in liver inflammation by promoting M1 macrophage polarization via RhoA/NF-κB p65 and ERK1/2 pathways, respectively, in mouse liver fibrogenesis. Front Immunol. 2017; 8:1214. https://doi.org/10.3389/fimmu.2017.01214

Tiyerili V, Zimmer S, Jung S, Wassmann K, Naehle CP, Lütjohann D et al. CB1 receptor inhibition leads to decreased vascular AT1 receptor expression, inhibition of oxidative stress and improved endothelial function. Basic Res Cardiol. 2010; 105:465–77. https://doi.org/10.1007/s00395-010-0090-7

Voicu V, Brehar F-M, Toader C, Covache-Busuioc R-A, Corlatescu AD, Bordeianu A et al. Cannabinoids in medicine: a multifaceted exploration of types, therapeutic applications, and emerging opportunities in neurodegenerative diseases and cancer. Biomolecules. 2023; 13(9):1388. https://doi.org/10.3390/biom13091388

Wang P-F, Jiang L-S, Bu J, Huang X-J, Song W, Du Y-P et al. Cannabinoid-2 receptor activation protects against infarct and ischemia-reperfusion heart injury. J Cardiovasc Pharmacol. 2012; 59(4):301–07. https://doi.org/10.1097/fjc.0b013e3182418997

Wang Y, Ma S, Wang Q, Hu W, Wang D, Li XJ et al. Effects of cannabinoid receptor type 2 on endogenous myocardial regeneration by activating cardiac progenitor cells in mouse infarcted heart. Sci China Life Sci. 2014; 57:201–08. https://doi.org/10.1007/s11427-013-4604-z

Wang Z, Wang X, Li J, Gong T, Li Q, Bu X et al. Effects of cannabidiol on growth performance, appetite, antioxidant capacity and liver inflammatory gene expression of juvenile large yellow croaker (Larmichthys crocea) fed diets with high soybean oil level. Aquaculture. 2023; 574:739658. https://doi.org/10.1016/j.aquaculture.2023.739658

Wu HM, Kim TH, Kim A, Koo JH, Joo MS, Kim SG. Liver X receptor α-induced cannabinoid receptor 2 inhibits ubiquitin-specific peptidase 4 through miR-27b, protecting hepatocytes from TGF-β. Hepatol Commun. 2019; 3(10):1373–87. https://doi.org/10.1002/hep4.1415

Xin Q, Xu F, Taylor DH, Zhao JF, Wu J. The impact of cannabinoid type 2 receptors (CB2Rs) in neuroprotection against neurological disorders. Acta Pharmacol Sin. 2020; 41:1507–18. https://doi.org/10.1038/s41401-020-00530-2

Yu W, Jin G, Zhang J, Wei W. Selective activation of cannabinoid receptor 2 attenuates myocardial infarction via suppressing NLRP3 inflammasome. Inflammation. 2019; 42:904–14. https://doi.org/10.1007/s10753-018-0945-x

Zoppi S, Nievas BGP, Madrigal JLM, Manzanares J, Leza JC, García-Bueno B. Regulatory role of cannabinoid receptor 1 in stress-induced excitotoxicity neuroinflammation. Neuropsychopharmacology. 2011; 36:805–18. https://doi.org/10.1038/npp.2010.214

Authors

Suzana Luisa Alves Fernandes¹, Yan Costa Gonçalves¹, Francisco Tadeu Rantin², Ana Lúcia Kalinin² and Diana Amaral Monteiro²

^[1]    Programa Interinstitucional de Pós-Graduação em Ciências Fisiológicas, Universidade Federal de São Carlos/ Universidade Estadual Paulista (PIPGCF UFSCar/UNESP), 13565-905 São Carlos, SP, Brazil. (SLAF) suzanafernandes@estudante.ufscar.br, (YCG) yancosta@estudante.ufscar.br.

^[2]    Departamento de Ciências Fisiológicas, Universidade Federal de São Carlos (UFSCar), 13565-905 São Carlos, SP, Brazil. (DAM) dianamonteiro@ufscar.br (corresponding author), (FTR) ftrantin@gmail.com, (ALK) akalinin@ufscar.br.

Authors’ Contribution

Suzana Luisa Alves Fernandes: Data curation, Formal analysis, Methodology, Visualization, Writing-original draft.

Yan Costa Gonçalves: Data curation, Formal analysis, Investigation, Methodology, Validation, Writing-original draft.

Francisco Tadeu Rantin: Resources, Validation, Visualization, Writing-original draft, Writing-review and editing.

Ana Lúcia Kalinin: Funding acquisition, Resources, Validation, Visualization, Writing-original draft, Writing-review and editing.

Diana Amaral Monteiro: Conceptualization, Data curation, Formal analysis, Funding acquisition, Investigation, Project administration, Supervision, Validation, Visualization, Writing-original draft, Writing-review and editing.

Ethical Statement​

Experiments were approved by the Ethical Committee for Animal Use in Experiments of the Universidade Federal de São Carlos (CEUA number 4997170718).

Competing Interests

The author declares no competing interests.

How to cite this article

Fernandes SLA, Gonçalves YC, Rantin FT, Kalinin AL, Monteiro DA. Activation of cannabinoid type 2 (CB2) receptors promotes the maintenance of redox homeostasis and protects against oxidative distress in the Neotropical freshwater fish matrinxã Brycon amazonicus (Characiformes: Bryconidae). Neotrop Ichthyol. 2024; 22(4):e240065. https://doi.org/10.1590/1982-0224-2024-0065

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